Microbiology Department, Hospital Clínic I Provincial de Barcelona, University of Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain.
National Reference Center for Herpesviruses, Microbiology Department, CHU Limoges, Limoges, France.
Microbiol Spectr. 2022 Apr 27;10(2):e0019122. doi: 10.1128/spectrum.00191-22. Epub 2022 Mar 28.
mutations in the terminase subunit and its associated phenotypes were studied in the context of cytomegalovirus (CMV) transplant recipients clinically resistant to DNA-polymerase inhibitors, naive to letermovir. R246C was the only variant detected by standard and deep sequencing, located within the letermovir-resistance-associated region (residues 230-370). R246C emerged in 2/80 transplant recipients (1 hematopoietic and 1 heart) since first cytomegalovirus replication and responded transiently to various alternative antiviral treatments . Recombinant phenotyping showed R246C conferred an advanced viral fitness and was sensitive to ganciclovir, cidofovir, foscarnet, maribavir, and letermovir. These results demonstrate a low rate (2.5%) of natural occurring polymorphisms within the letermovir-resistant-associated region before its administration. Identification of high replicative capacity variants in patients not responding to treatment or experiencing relapses could be helpful to guide further therapy and dosing of antiviral molecules. We provide comprehensive data on the clinical correlates of both CMV genotypic follow-up by standard and deep sequencing and the clinical outcomes, as well as recombinant phenotypic results of this novel mutation. Our study emphasizes that the clinical follow-up in combination with genotypic and phenotypic studies is essential for the assessment and optimization of patients experiencing HCMV relapses or not responding to antiviral therapy. This information may be important for other researchers and clinicians working in the field to improve the care of transplant patients since drug-resistant CMV infections are an important emerging problem even with the new antiviral development.
在针对对 DNA 聚合酶抑制剂具有临床耐药性、对勒特莫韦无耐药史的移植受者中，研究了终止酶亚基及其相关表型的突变与巨细胞病毒（CMV）的关系。标准和深度测序仅检测到 R246C 这一种变异，该变异位于勒特莫韦耐药相关区域（残基 230-370）内。自首次出现巨细胞病毒复制以来，2/80 例（1 例造血和 1 例心脏）移植受者中出现了 R246C，对各种替代抗病毒治疗的反应短暂。重组表型研究显示，R246C 赋予了病毒较高的适应性，对更昔洛韦、西多福韦、膦甲酸钠、马拉韦罗和勒特莫韦敏感。这些结果表明，在使用勒特莫韦之前，耐药相关区域内自然发生的多态性发生率较低（2.5%）。对于未对治疗产生反应或出现复发的患者，识别具有高复制能力的变异体有助于指导进一步的治疗和抗病毒药物的剂量调整。我们提供了有关 CMV 基因型通过标准和深度测序进行随访的临床相关性、临床结果以及该新型突变的重组表型结果的综合数据。我们的研究强调，临床随访与基因型和表型研究相结合，对于评估和优化出现 HCMV 复发或对抗病毒治疗无反应的患者至关重要。对于在该领域工作的其他研究人员和临床医生来说，这些信息可能非常重要，因为即使有新的抗病毒药物发展，耐药性 CMV 感染仍是一个重要的新问题。
